Abstract 187: Host Age Enhances Atherosclerotic Plaque Necrosis and Macrophage Infiltration in Mice Independently of Metabolic Alterations

Abstract

Traditional murine models of atherosclerosis age with mild hypercholesterolemia and metabolic derangement, which confounds determination of the intrinsic effects of aging on atherogenesis. To examine if host age enhances atherogenesis independently of metabolic alterations, we induced hypercholesterolemia in wild-type (WT) aging mice using a PCSK9 adeno-associated viral approach. Intraperitoneal PCSK9 transfection and high-fat (42% fat) feeding led to similar elevated blood cholesterol levels between young (3-months) and aged (18-months) WT mice, which were also similar to young low-density lipoprotein receptor knockout (LDLR -/- ) mice fed the same high-fat diet within 2 weeks. Elevated cholesterol levels persisted during the 10-week feeding period. Although aged mice exhibited an elevated body weight at baseline, both groups gained the same amount of weight during the high-fat feeding. Glucose and insulin resistance measured via tolerance tests were dysregulated but similar between young and aged mice. We next measured atherosclerotic plaque size and composition using H and E, Masson's trichrome, and immunohistochemical staining along with flow cytometry. There was no difference in total plaque size in the aortic sinus between the groups; however, the atherosclerotic necrotic core size and macrophage staining was significantly greater in aged mice. Flow cytometry revealed greater numbers of inflammatory monocytes in the blood along with increased macrophage infiltration in the aorta of aged hyperlipidemic mice compared to young mice. We conclude that aging induces inflammatory monocytosis and macrophage infiltration during atherosclerosis, resulting in increased plaque necrosis and progression of atherosclerosis, independently of confounding metabolic alterations. Our results indicate that aging directly impacts atherogenesis by increasing plaque instability.